Abstract 5927: Leveraging single cell RNA profiling to uncover intra-tumor heterogeneity across cytogenetic subgroups in acute myeloid leukemia
Authors: Bofei Wang, Christopher Ly, Fatima Zahra Jelloul, Enes Dasdemir, Guilin Tang, Sonali Jindal, Yulong Chen, Sreyashi Basu, Poonam Desai, Pamella Borges, Preethi Gunaratne, Natalia Baran, Qing Deng, Dapeng Hao, Sean Post, Michael Green Green, Marina Konopleva, Andy Futreal, Padmanee Sharma, Hussein A. Abbas
Journal: Cancer Research (2023)

Abstract Acute Myeloid Leukemia (AML) is a heterogenous disease characterized by immature blasts at different states of differentiation resulting in marked intra-tumor heterogeneity (ITH). Compared to patients with diploid cytogenetics, deletions in chromosome 7/7q (del7/7q), 5/5q (del5/5q) or double deletion (del5/5q &amp; del 7/7q) confer worse outcomes in AML. We conducted single cell RNA (scRNA) profiling of bone marrow mononulear cells (BMMCs) from 20 newly diagnosed adult AML patients with diploid (n=7), del5/5q (n=5), del7/7q (n=5) and double deletion (n=3) to uncover ITH within each group and reveal cellular hierarchies associated with inferred copy number variations (CNV). Diffusion map analysis revealed heterogenous gene expression pattern in AML cells of del7/7q and double deletion patients, compared to diploid and del5/5q patients. CNV-based subgrouping of AML cells revealed significant enrichment of antigen presentation and immune response pathways in cells with inferred del7/7q or double deletion compared to cells without these deletions in the same patients, suggesting a heterogenous immune state in AML cells correlating with inferred genomic copy numbers. To dissect the composition of cellular hierarchies, AML cells were then projected onto an independent healthy BMMC reference (&amp;gt20,000 cells) and labeled based on transcriptional similarity to healthy hematopoietic cells. AML cells from diploid patients were enriched for GMP-like and monocyte-like cells, while cells from non-diploid patients were enriched in more primitive states (HSC-like and CMP/LMPP-like). Correlating these hierarchal groups with leukemic stem cell (LSC) hierarchies revealed shared transcriptional program in LSC-like states across HSC-like, GMP-like, CLP-like and erythroid-like cells. This suggests that LSC signatures can also be expressed across AML cells and not just primitive cells. These findings were also validated in deconvolution analysis of bulk transcriptomes from three independent newly diagnosed AML cohorts (TCGA, BEAT-AML and MDACC). Spatial deconvolution of 3 patients using whole transcriptomic GeoMx revealed that primitive cells were more likely to be proximal to bone, while more differentiated states were enriched in distal region from the bone. Our findings reveal complex hierarchies in AML cells sharing the LSC expression pattern, while more primitive cells were likely to localize to bone regions suggesting spatial migration of AML cells at time of differentiation. Citation Format: Bofei Wang, Christopher Ly, Fatima Zahra Jelloul, Enes Dasdemir, Guilin Tang, Sonali Jindal, Yulong Chen, Sreyashi Basu, Poonam Desai, Pamella Borges, Preethi Gunaratne, Natalia Baran, Qing Deng, Dapeng Hao, Sean Post, Michael Green Green, Marina Konopleva, Andy Futreal, Padmanee Sharma, Hussein A. Abbas. Leveraging single cell RNA profiling to uncover intra-tumor heterogeneity across cytogenetic subgroups in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5927.